Inflammation, or the "inflammatory response", is the result of complex interconnected physiological events, including increased vascular permeability, fluid accumulations, and the migration of a changing population of inflammatory cells into the inflamed area. The clinical manifestations of inflammation include swelling (edema), increased local temperature, erythema, and pain. The inflammatory response can be triggered by any of a number of causative factors, including certain bacteria, radiation, hypersensitivity to chemical agents, arthritis-like conditions, and the like. The inflammatory response is generally believed to be a primary defense mechanism in the body, but, unchecked, can become excessive and can result in functional impairment.
The use of non-steroidal anti-inflammatory, anti-pyretic and analgesic drugs, especially the salicylates, which include aspirin and aspirin derivatives, to combat inflammation and attendant pain is accepted medical practice. The non-steroidals are commonly employed to relieve pain and inflammation associated with, for example, bursitis, arthritis, and the like.
While pain is incapable of precise definition due to its basically subjective nature, it can generally be said that the term refers to feelings of distress or suffering caused by stimulation of specialized nerve endings. A great variety of drugs have been developed to reduce pain in man and other animals; some directed to eliminating pain at its source, and others directed to blocking the assimilation of pain by the brain. Among the latter group of drugs that are designed to block the sensation of pain, are the analgesics, which generally relieve pain without causing unconsciousness. Analgesics can be further classified in two main categories: opioid analgesics, including morphine, codeine, levorphanol, and the morphine-like analgesics meperidine, and methadone; and antipyretic analgesics, such as aspirin, ibuprofen, phenacetin, acetaminophen, phenylbutazone, and indomethacin.
Although the precise pharmacological action of these analgesics is uncertain, there are certain effects which readily distinguish the opioid analgesics from the antipyretics. In particular, the antipyretics are weak analgesics, with much of their effect in the peripheral nervous system, so that behavioral changes do not usually occur. Generally, these analgesics relieve only somatic pain originating from muscles, joints, tendons and fasciae, and are ineffective against deep visceral pain. However, the opioid analgesics are quite effective against all types of pain, with broad-based action in the central nervous system. Aside from potent analgesia, the opioids, also known as narcotics, often produce effects on mood and other behavioral changes. Perhaps the most notable side effect of the opioid analgesics is the fact that their repeated use is associated with tolerance, as well as psychic and physical dependence.
It has been recently discovered that capsaicin, a natural product of certain species of the genus Capsicium, induces analgesia. Capsaicin (trans-8-methyl-N-vanillyl-6-nonenanamide) and "synthetic" capsaicin (N-vanillylnonanamide) are disclosed as analgesics in U.S. Pat. No. 4,313,958, LaHann, issued Feb. 2, 1982. Analgesic activity of capsaicin has also been discussed in the chemical and medical literature, including Yaksh, et al, Science, 206, pp 481-483 (1979); Jancso, et al, Naunyn-Schmiedeberg's Arch. Pharmacol., Vol. 311, pp 285-288 (1980) and Holzer et al, Eur. J. Pharm. Vol. 58, pp 511-514 (1979). U.S. Pat. No. 4,238,505, Nelson, issued Dec. 9, 1980, discloses 3-hydroxyacetanilide for use in producing analgesia in animals. European Patent Application No. 0089710, LaHann, et al, published Sept. 28, 1983, describes hydroxyphenylacetamides with analgesic and anti-irritant activity. Similarly, analgesic and anti-irritant activity is disclosed for N-vanillyl sulfonamides in U.S. Pat. No. 4,401,663, Buckwalter, et al, issued Aug. 30, 1983; hydroxyphenyl-acetamides in U.S. Pat. No. 4,424,205, LaHann, et al, issued Jan. 31, 1984; N-(3- or 4- hydroxy or 3,4-dihydroxybenzyl) carbamates in U.S. Pat. No. 4,443,473, Buckwalter, et al, issued Apr. 17, 1984; N-[(substituted phenyl) methyl]-cis-monounsaturated alkenamides in U.S. Pat. No. 4,493,848, LaHann, et al, issued Jan. 15, 1985; N-(3-methoxy-4-hydroxybenzyl and phenyl) ureas and thioureas in U.S. Pat. No. 4,460,602, Buckwalter, et al, issued Jul. 17, 1984; N-vanillylureas in European Patent Application No. 0068590, Buckwalter, et al, published Jan. 5, 1983; N-[(substituted phenyl)methyl] alkynamides in U.S. patent application Ser. No. 514,204, Janusz, et al, filed Jul. 14, 1983; methylene substituted N-[(substituted phenyl)methyl] alkanamides in U.S. patent application Ser. No. 514,205, Janusz, et al, filed Jul. 14, 1983; N-[(substituted phenyl) methyl]-diunsaturated amides in U.S. patent application Ser. No. 514,207, LaHann, et al, filed Jul. 14, 1983; monoalkenamides in U.S. patent application Ser. No. 676,025, LaHann, et al, filed Nov. 28, 1984; trienamides in U.S. patent application Ser. No. 684,427, Janusz, et al, filed Dec. 20, 1984; substituted phenylacetic acid esters in U.S. patent application Ser. No. 684,428, Loomans, et al, filed Dec. 20, 1984; N-(substituted alkyl)alkanamides and thioamides in U.S. patent application Ser. No. 684,429, Loomans, et al, filed Dec. 20, 1984; substituted aromatic-araalkanamides in U.S. patent application Ser. No. 684,430, Janusz et al, filed Dec. 20, 1984; and combinations of capsaicinoids and arylalkanoic acids in U.S. patent application Ser. No. 684,642, Brand, filed Dec. 24, 1984.
It has now been discovered that certain substituted phenylacetic acid amides have anti-inflammatory and analgesic activity in humans and lower animals. Some of these substituted phenylacetic acid amide compounds have analgesic potency far greater than that of aspirin and comparable to that of the opioids, but do not exhibit undesirable narcotic side effects such as tolerance and physical dependence. These substituted phenylacetic acid amide compounds are also less toxic than capsaicin.
U.S. Pat. No. 4,493,848 discloses analgesic compounds, many of which are reverse amides of the compounds of the present invention. Surprisingly, however, the compounds of the present invention notwithstanding their close structural similarity to the compounds described in the aforementioned U.S. Patent, demonstrate greatly enhanced analgesic efficacy when taken orally. Additionally, for capsaicinoids of the prior art, it has been found that the "cis" (or Z) stereoisomers have an analgesic activity significantly greater than that of their "trans" (or E) isomers. Surprisingly, the cis and trans isomers of the substituted phenylacetic acid amide compounds of the present invention are approximately equipotent exhibiting strong analgesic activity.
The "cis" prefix is used in designating geometrical isomers in which there is a double bond between two carbon atoms and wherein the primary substituent group for each of the two carbon atoms is on the same side of the double bond axis. Conversely, the "trans" isomer designates a spatial arrangement wherein the primary substituent groups on each of the two carbon atoms in the double bond are on opposite sides of the bond axis.